Compounds and methods for treating transplant rejection

ABSTRACT

The use of compounds of the formula  
                 
 
     and pharmaceutically acceptable salts thereof, alone or in combination for the treatment of transplant rejection, wherein the substituents are further defined in the application.

COMPOUNDS AND METHODS FOR TREATING TRANSPLANT REJECTION

[0001] This application claims priority to U.S. patent application Ser.No. 09/370,046, filed Aug. 6, 1999, which is a continuation of U.S.patent application Ser. No. 09/079,213, now U.S. Pat. No. 6,147,250,which claims priority to U.S. patent application Ser. No. 60/047,020filed May 14, 1997. This application also claims priority, as acontinuation-in-part, to U.S. patent application Ser. No. 09/815,262,filed Mar. 21, 2001, and to U.S. patent application Ser. No. 60/191,046,filed Mar. 21, 2000.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The current invention provides compounds, compositions andmethods to modulate organ and tissue transplant rejection and prolongthe survival of transplanted organs and tissues.

[0004] 2. Background Art

[0005] Organ and tissue transplantation has become a standard surgicalprocedure. In 1990, 15,000 organ transplantations were performed, and by1999, this number was up to 21,000. The success of surgicaltransplantation of organs and tissue is largely dependent on the abilityof the clinician to modulate the immune response of the transplantrecipient. Specifically the immunological response directed against thetransplanted foreign tissue must be controlled if the tissue is tosurvive and function. Currently, skin, kidney, liver, pancreas, lung andheart are the major organs or tissues with which allogeneictransplantations are performed. It has long been known that the normallyfunctioning immune system of the transplant recipient recognizes thetransplanted organ as “non-self” tissue and thereafter mounts an immuneresponse to the presence of the transplanted organ. Left unchecked, theimmune response will generate a plurality of cells and proteins thatwill ultimately result in the loss of biological functioning or thedeath of the transplanted organ.

[0006] This tissue/organ rejection can be categorized into three types:hyperacute, acute and chronic. Hyperacute rejection is essentiallycaused by circulating antibodies in the blood that are directed againstthe tissue of the transplanted organ (transplant). Hyperacute rejectioncan occur in a very short time—often in minutes—and leads to necrosis ofthe transplant. Acute graft rejection reaction is also immunologicallymediated and somewhat delayed compared to hyperacute rejection. Thechronic form of graft rejection that can occur years after thetransplant is the result of a disease state commonly referred to asGraft Arterial Disease (GAD). GAD is largely a vascular diseasecharacterized by neointimal proliferation of smooth muscle cells andmononuclear infiltrates in large and small vessels. This neointimalgrowth can lead to vessel fibrosis and occlusion, lessening blood flowto the graft tissue and resulting in organ failure. Currentimmunosuppressant therapies do not adequately prevent chronic rejection.Most of the gains in survival in the last decade are due to improvementsin immunosuppressive drugs that prevent acute rejection. However,chronic rejection losses remain the same and drugs that can prevent itare a critical unmet medical need.

[0007] It is additionally known that the transplant-host relationship isnot restricted to rejection by the host organism alone; in certain casesan immune reaction originating from the transplant and directed againstthe host tissue (Graft versus Host Disease (GVHD)) can occur(EP-A-217,206). A differentiation is therefore made between a rejectionbetween transplant and host and between host and transplant.

[0008] Tissue and organ transplant recipients are customarily treatedwith one or more cytotoxic agents in an effort to suppress thetransplant recipient's immune response against the transplanted organ ortissue. Current immunosuppressant drugs include: cyclosporin, tacrolimus(FK506), sirolimus (rapamycin), methotrexate, mycophenolic acid(mycophenolate mofetil), everolimus, azathiprine, steroids and NOX-100.All of these drugs have side effects (detailed below) that complicatetheir long-term use. For example, cyclosporin (cyclosporin A), a cyclicpolypeptide consisting of 11 amino acid residues and produced by thefungus species Tolypocladium inflatum Gams, is currently the drug ofchoice for administration to the recipients of allogeneic kidney, liver,pancreas and heart (i.e., wherein donor and recipient are of the samespecies of mammals) transplants. However, administration of cyclosporinis not without drawbacks as the drug can cause kidney and liver toxicityas well as hypertension. Moreover, use of cyclosporin can lead tomalignancies (such as lymphoma) as well as opportunistic infection dueto the “global” nature of the immunosuppression it induces in patientsreceiving long term treatment with the drug, i.e., the hosts normalprotective immune response to pathogenic microorganisms is downregulatedthereby increasing the risk of infections caused by these agents.

[0009] FK506 (tacrolimus) has also been employed as an immunosuppressiveagent as a stand-alone treatment or in combination. Although itsimmunosuppressive activity is 10-100 times greater than cyclosporin, itstill has toxicity issues. Known side effects include kidney damage,seizures, tremors, high blood pressure, diabetes, high blood potassium,headache, insomnia, confusion, seizures, neuropathy, and gout. It hasalso been associated with miscarriages.

[0010] Methotrexate is commonly added to the treatment of the cytotoxicagent. Methotrexate is given in small doses several times after thetransplant. Although the combination of cyclosporin and methotrexate hasbeen found to be effective in decreasing the severity of transplantrejection, there are side effects, such as mouth sores and liver damage.

[0011] Severe transplant rejection can be treated with steroids.However, the side effects of steroids can be extreme, such as weightgain, fluid retention, elevated blood sugar, mood swings, and/orconfused thinking.

[0012] Rapamycin, a lipophilic macrolide used as an anti-rejectionmedication can be taken in conjunction with other anti-rejectionmedicines (i.e., cyclosporin) to reduce the amount of toxicity of theprimary cytotoxic agent, but it too has specific side effects, such ascausing high cholesterol, high triglycerides, high blood pressure, rashand acne. Moreover, it has been associated with anemia, joint pain,diarrhea, low potassium and a decrease in blood platelets.

[0013] Vitamin D has been employed to decrease bone loss caused bycyclosporin (U.S. Pat. No. 6,071,897) and was shown to decrease thepossibility of infection noted by the use of cyclosporin.

[0014] Although many approaches have been conceived to treat transplantrejection, there is still room for improvement. (See U.S. Pat. Nos.6,239,124, 6,071,897, 5,788,968, 5,728,721, 5,308,847, 5,298,523,5,212,155, 5,100,899 all herein incorporated by reference in theirentirety.)

[0015] U.S. Pat. No. 5,262,439 to Parthasarathy, which is assigned toAtheroGenics, Inc. discloses analogs of probucol with increased watersolubility in which one or both of the hydroxyl groups are replaced withester groups that increase the water solubility of the compound. In oneembodiment, the derivative is selected from the group consisting of amono- or di-probucol ester of succinic acid, glutaric acid, adipic acid,seberic acid, sebacic acid, azelaic acid, or maleic acid. In anotherembodiment, the probucol derivative is a mono- or di-ester in which theester contains an alkyl or alkenyl group that contains a functionalityselected from the group consisting of a carboxylic acid group, aminegroup, salt of an amine group, amide groups, amide groups, and aldehydegroups.

[0016] U.S. Pat. No. 6,121,319, which issued on Sep. 19, 2000, andcorresponding WO 98/51662 filed by AtheroGenics, Inc. and published onNov. 18, 1998, describes certain compounds of formula having thestructure

[0017] wherein:

[0018] R_(a), R_(b), R_(c), and R_(d) are independently any group thatdoes not otherwise adversely affect the desired properties of themolecule, including hydrogen, straight chained, branched, or cyclicalkyl which may be substituted, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl orsubstituted aralkyl; substituents on the R_(a), R_(b), R_(c) and R_(d)groups are selected from the group consisting of hydrogen, halogen,alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, andacyloxy;

[0019] Z is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, acarbohydrate group, —(CH₂)—R_(e), —C(O)—R_(g), and—C(O)—(CH₂)_(n)—R_(h), wherein (a)

[0020] when each of R_(a), R_(b), R_(c), and R_(d) are t-butyl, Z cannotbe hydrogen; and

[0021] the other variables are as defined in those specifications, forthe treatment of disorders mediated by VCAM-1, and inflammatory andcardiovascular disorders.

[0022] WO 01/70757 filed by AtheroGenics, Inc. and published on Sep. 27,2001, describes the use of certain thioethers of the following formula,and pharmaceutically acceptable salts thereof:

[0023] wherein

[0024] a) R_(a), R_(b), R_(c), and R_(d) are independently any groupthat does not adversely affect the desired properties of the molecule,including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl,aralkyl, or substituted aralkyl; and

[0025] b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) asubstituted or unsubstituted alditol, (iii) C₁₋₁₀alkyl or substitutedC₁₋₁₀alkyl, terminated by sulfonic acid, (iv) C₁₋₁₀alkyl or substitutedC₁₋₁₀alkyl, terminated by phosphonic acid, (v) substituted orunsubstituted C₁₋₁₀alkyl—O—C(O)—C₁₋₁₀alkyl, (vi) straight chainedpolyhydroxylated C₃₋₁₀alkyl; (vii)—(CR₂)₁₋₆—COOH, wherein R isindependently hydrogen, halo, amino, or hydroxy, and wherein at leastone of the R substituents is not hydrogen; or (viii) —(CR₂)₁₋₆—X,wherein X is aryl, heteroaryl, or heterocycle, and R is independentlyhydrogen, halo, amino, or hydroxy.

[0026] for use in treating organ transplant rejection.

[0027] Given the strong side effects of the current drugs, typicallyimmunosuppressant drugs, that are now commonly used in treating solidorgan transplant rejection, there is a strong need to provide newmethods in the tissue and transplant field that have low toxicity andare effective in transplant rejection either alone or in combinationwith known treatment regimens.

BRIEF SUMMARY OF THE INVENTION

[0028] The present invention provides a method of inhibiting organ ortissue transplant rejection in a mammal, either alone or in combinationwith other medications, wherein the method comprises administering acompound of the formula

[0029] or a pharmaceutically acceptable salt thereof wherein:

[0030] Y is a bond or

[0031] R₁, R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, hydroxy, C₁₋₁₀alkyl, aryl, heteroaryl,C₁₋₁₀alkaryl, and aryl C₁₋₁₀alkyl, wherein all nonhydrogen and hydroxysubstituents may optionally be substituted from one or more of the groupselected from C₁₋₁₀alkyl, halogen, nitro, amino, haloC₁₋₁₀alkyl,C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0032] Z is selected from the group consisting of C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl, aryl, heteroaryl,C₁₋₁₀alkaryl, arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylaminoC₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carboxy, carbohydrate group,carbohydrate lactone group, and an alditol group wherein all mayoptionally be substituted by one or more R₅;

[0033] R₅ is independently selected from the group selected fromhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, halo, nitro, amino, cyano,C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, PO₂H₂P(O)(OH)R₇, P(O)(OR₇)₂,P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate, whereinwhen possible, all may be optionally substituted by one or more R₆;

[0034] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0035] R₇ is independently selected from the group consisting ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0036] R₈ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,and carboxy;

[0037] wherein two R₇ groups may come together to form a 4 to 7 memberedring.

[0038] The present invention also provides a method of moderatingtransplant rejection and a method to increase transplant survival. Otheradvantages of the invention will become clearer in light of the detaileddescription, drawings and claims.

[0039] This method can be used to treat tissue/organ rejectioncategorized as either or a combination of hyperacute, acute and chronic.The invention is particularly useful in treating the chronic form oforgan rejection, and in particular Graft Arterial Disease. The methodcan be used to treat rejection of any organ, and in particular, skin,kidney, liver, pancreas, lung and heart.

[0040] The invention also includes pharmaceutical compositions suitablefor the treatment of transplant rejection.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041]FIG. 1 is a bar chart graph showing the mean intima-to-media ratiomeasured 90 days post operation versus dosage.

[0042]FIG. 2 shows the percent luminal narrowing of the graft section 90days post operation.

[0043]FIG. 3 is a graph of the relative plasma levels of Compound Afound in the groups of animals 7, 14, 30, 60, and 90 days aftersubcutaneous administration in PTC/saline 1:5 vehicle.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention addresses the need for an alternate methodof treating organ and tissue transplant rejection. The method providesmeans whereby the rejection of tissue or organs after transplantationcan be prevented or controlled, thus prolonging the survival of thetissue or organ. The present invention can be used in hyperacute, acuteand chronic rejection of tissue or organs. Combinations of drugs andtreatment regimens are also contemplated by the invention.

[0045] Many of the compounds used in the invention are described indetail in U.S. Pat. No. 6,147,250, herein incorporated by reference inits entirety.

[0046] Suitable compounds of the invention are described by thefollowing formula

[0047] or a pharmaceutically acceptable salt thereof wherein:

[0048] Y is a bond or

[0049] R₁, R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, hydroxy, C₁₋₁₀alkyl, aryl, heteroaryl,C₁₋₁₀alkaryl, and aryl C₁₋₁₀alkyl, wherein all nonhydrogen and hydroxysubstituents may optionally be substituted from one or more of the groupselected from C₁₋₁₀alkyl, halogen, nitro, amino, haloC₁₋₁₀alkyl,C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0050] Z is selected from the group consisting of C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl, aryl, heteroaryl,C₁₋₁₀alkaryl, arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylaminoCl₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carboxy, carbohydrate group,carbohydrate lactone group, and an alditol group wherein all mayoptionally be substituted by one or more R₅;

[0051] R₅ is independently selected from the group selected fromhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, halo, nitro, amino, cyano,C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, PO₂H₂P(O)(OH)R₇, P(O)(OR₇)₂,P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate, whereinwhen possible, all may be optionally substituted by one or more R₆;

[0052] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0053] R₇ is independently selected from the group consisting ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0054] R₈ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,and carboxy;

[0055] wherein two R₇ groups may come together to form a 4 to 7 memberedring.

[0056] In a narrower embodiment, the compound may be chosen from theformula

[0057] or a pharmaceutically acceptable salt wherein:

[0058] Y is a bond;

[0059] Z is selected from the group consisting of C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl, aryl, heteroaryl,C₁₋₁₀alkaryl, arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylaminoC₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carbohydrate group, carbohydratelactone group, and an alditol group wherein all may optionally besubstituted by one or more R₅;

[0060] R₅ is independently selected from the group selected fromhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, halo, nitro, amino, cyano,C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, PO₂H₂P(O)(OH)R₇, P(O)(OR₇)₂,P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate, whereinwhen possible, all may be optionally substituted by one or more R₆;

[0061] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0062] R₇ is independently selected from the group consisting ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0063] R₈ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,and carboxy;

[0064] wherein two R₇ groups may come together to form a 4 to 7 memberedring.

[0065] In another embodiment of the above formula, Z is selected fromthe group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, and carboxyC₁₋₆alkyl, wherein all may optionally besubstituted by one or more R₅;

[0066] R₅ is independently selected from the group selected fromhydroxy, amino, halo, COOH, COOR₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂,C(O)NHR₇, CONR₇R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇,P(O)(OH)R₇, P(O)HR₇, P(OR₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂, andhydroxymethyl, wherein when possible, all may be optionally substitutedby one or more R₆;

[0067] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0068] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkoxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, andC₁₋₆alkylcarboxyC₁₋₆alkyl, wherein all may be optionally substituted byone or more R₈; and

[0069] R₈ is independently selected from the group consisting ofhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano, andcarboxy.

[0070] In another embodiment of the above formula, Z is C₁₋₆alkyl,optionally substituted by one or more R₅;

[0071] R₅ is independently selected from the group consisting of halo,COOH, COOR₇, CONH₂, CONHR₇, CONR₇R₇, and amino;

[0072] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, carboxyC₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, andC₁₆alkylcarboxyC₁₋₆alkyl, wherein all may be optionally substituted byone or more R₈; and

[0073] R₈ is independently selected from the group consisting ofhydroxy, halo, amino, and carboxy.

[0074] In another embodiment of the above formula, Z is C₁₋₆alkyl,optionally substituted by one or more R₅; and

[0075] R₅ is COOH.

[0076] Specific compounds of the above formula are

[0077] In another embodiment of the above formula, Z is an alditol,optionally substituted with one or more R₅; and

[0078] R₅ is independently selected from the group consisting of halo,amino, carboxy, diC₁₋₆alkylamino, and C₁₋₆alkylamino.

[0079] Specific compounds of the above formula are

[0080] In another embodiment of the above formula, Z is a carbohydrateor a carbohydrate lactone, optionally substituted by one or more R₅; and

[0081] R₅ is independently selected from the group consisting of halo,amino, carboxy, diC₁₋₆alkylamino, acyloxy, and C₁₋₆alkylamino.

[0082] Specific compounds of the above formula are

[0083] In yet another embodiment of the above formula, Z is selectedfrom the group consisting of C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkylaminoC₁₋₆alkyl, C₁₋₆dialkylaminoC₁₋₆alkyl,and aminoC₁₋₆alkyl,wherein all may optionally be substituted by one or more R₅;

[0084] R₅ is independently selected from the group selected fromhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, nitro, amino, cyano,C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—

[0085] R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, P(O)HR₇,P(O)(OH)R₇, P(OR₇)₂,

[0086] P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate,wherein when possible, all may be optionally substituted by one or moreR₆;

[0087] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano,haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, and acyloxy;

[0088] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, carboxyC₁₋₆alkyl,C₁₋₆alkylcarboxyC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0089] R₈ is independently selected from the group consisting ofhydroxy, halo, amino, and carboxy

[0090] Specifically, the compound may be chosen from

[0091] In another embodiment of the above formnula, Z is selected fromthe group consisting of C₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkaryl,arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, heterocycle, andheterocyclC₁₋₆alkyl, wherein all may optionally be substituted by one ormore R₅;

[0092] R₅ is independently selected from the group selected fromhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, nitro, amino, cyano,C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—

[0093] R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, P(O)HR₇,P(O)(OH)R₇)₂,

[0094] P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate,wherein when possible, all may be optionally substituted by one or moreR₆;

[0095] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano,haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, and acyloxy;

[0096] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₆alkyl,C₁₋₆alkylcarboxyC₁₋₆alkyl, C₁₋₆alkylcarboxyC₁₋₆aryl, heterocycle,heterocyclC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0097] R₈ is independently selected from the group consisting ofhydroxy, halo, amino, and carboxy;

[0098] wherein two R₇ groups may come together to form a 4 to 7 memberedring.

[0099] In another embodiment of the invention, the compound may bechosen from the following formula

[0100] or a pharmaceutically acceptable salt wherein:

[0101] Z is selected from the group consisting of C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl, aryl, heteroaryl,C₁₋₁₀alkaryl, arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylaminoC₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carboxy, carbohydrate group,carbohydrate lactone group, and an alditol group wherein all mayoptionally be substituted by one or more R₅;

[0102] R₅ is independently selected from the group selected fromhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, halo, nitro, amino, cyano,C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, PO₂H₂P(O)(OH)R₇, P(O)(OR₇)₂,

[0103] P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate,wherein when possible, all may be optionally substituted by one or moreR₆;

[0104] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, and acyloxy;

[0105] R₇ is independently selected from the group consisting ofC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0106] R₈ is independently selected from the group consisting ofhydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo, nitro, amino, cyano,and carboxy;

[0107] wherein two R₇ groups may come together to form a 4 to 7 memberedring.

[0108] In another embodiment of the above formula, Z is selected fromthe group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, and carboxyC₁₋₆alkyl, wherein all may optionally besubstituted by one or more R₅;

[0109] R₅ is independently selected from the group selected fromhydroxy, amino, halo, COOH, COOR₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂,C(O)NHR₇, CONR₇R₇, OS₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇,P(O)(OH)R₇, P(O)HR₇, P(OR₇)₂, P(O)R₇(OR)₇), OPO₃H, PO₃H₂, andhydroxymethyl, wherein when possible, all may be optionally substitutedby one or more R₆;

[0110] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkoxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, andC₁₋₆alkylcarboxyC₁₋₆alkyl, wherein all may be optionally substituted byone or more R₈; and

[0111] R₈ is independently selected from the group consisting ofhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano, andcarboxy.

[0112] In another embodiment of the above formula c, Z is C₁₋₆alkyl,optionally substituted by one or more R₅;

[0113] R₅ is independently selected from the group consisting of halo,COOH, COOR₇, CONH₂, CONHR₇, CONR₇R₇, and amino;

[0114] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, carboxyC₁₋₆alkyl, and C₁₋₆alkylcarboxyC₁₋₆alkyl, wherein allmay be optionally substituted by one or more R₈; and

[0115] R₈ is independently selected from the group consisting ofhydroxy, halo, amino, and carboxy.

[0116] In another embodiment of the above formula, Z is C₁₋₆alkyl,optionally substituted by one or more R₅; and R₅ is COOH.

[0117] Specifically, the compound may be chosen from

[0118] In another embodiment of the above formula, Z is selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkylaminoC₁₋₆alkyl, and aminoC₁₋₆alkyl, wherein all may optionallybe substituted by one or more R₅;

[0119] R₅ is independently selected from the group selected fromhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, nitro, amino, cyano,C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, P(O)HR₇, P(O)(OH)R₇, P(OR₇)₂,P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate, whereinwhen possible, all may be optionally substituted by one or more R₆;

[0120] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano,haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, and acyloxy;

[0121] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, carboxyC₁₋₆alkyl, Cl₆alkylcarboxyC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0122] R₈ is independently selected from the group consisting ofhydroxy, halo, amino, and carboxy

[0123] In another embodiment of the above formula, the compound may be

[0124] In another embodiment of the above formula, Z is selected fromthe group consisting of C₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkaryl,arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, heterocycle, andheterocyclC₁₋₆alkyl, wherein all may optionally be substituted by one ormore R₅;

[0125] R₅ is independently selected from the group selected fromhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, nitro, amino, cyano,C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, P(O)HR₇, P(O)(OH)R₇)₂,P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate, whereinwhen possible, all may be optionally substituted by one or more R₆;

[0126] R₆ is independently selected from the group consisting ofhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano,haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, and acyloxy;

[0127] R₇ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₆alkyl,C₁₋₆alkylcarboxyC₁₋₆alkyl, C₁₋₆alkylcarboxyC₁₋₆aryl, heterocycle,heterocyclC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and

[0128] R₈ is independently selected from the group consisting ofhydroxy, halo, amino, and carboxy;

[0129] wherein two R₇ groups may come together to form a 4 to 7 memberedring.

[0130] The term “alkyl”, alone or in combination, means an acyclic,saturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon, including those containing from 1 to 10 carbon atoms orfrom 1 to 6 carbon atoms. Said alkyl radicals may be optionallysubstituted with groups as defined below. Examples of such radicalsinclude methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl,isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,aminopentyl, iso-amyl, hexyl, octyl and the like.

[0131] The term “alkylene” radical denotes linear or branched radicalsincluding having from 2 to 10 carbon atoms or 2 to 6 carbon atoms andhaving attachment points for two or more covalent bonds. Examples ofsuch radicals are methylene, ethylene, methylethylene, andisopropylidene.

[0132] The term “alkynyl” refers to an unsaturated, acyclic hydrocarbonradical, linear or branched, in so much as it contains one or moretriple bonds, including such radicals containing about 2 to 10 carbonatoms or having from 2 to 6 carbon atoms. Said alkynyl radicals may beoptionally substituted with groups as defined below. Examples ofsuitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl,butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl,3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl,3,3-dimethylbutyn-1-yl radicals and the like.

[0133] The term “acyl”, alone or in combination, means a carbonyl orthionocarbonyl group bonded to a radical selected from, for example,hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl,haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy,arylthio, and alkylthioalkyl. Examples of “acyl” are formyl, acetyl,benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.

[0134] The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. The term “alkoxyalkyl” alsoembraces alkyl radicals having one or more alkoxy radicals attached tothe alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. Other alkoxy radicals are “lower alkoxy” radicals having oneto six carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy alkyls. The “alkoxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropoxy.

[0135] The term “alkylamino” denotes “monoalkylamino” and “dialkylamino”containing one or two alkyl radicals, respectively, attached to an aminoradical. The terms arylamino denotes “monoarylamino” and “diarylamino”containing one or two aryl radicals, respectively, attached to an aminoradical. The term “Aralkylamino”, embraces aralkyl radicals attached toan amino radical. The term aralkylamino denotes “monoaralkylamino” and“diaralkylamino” containing one or two aralkyl radicals, respectively,attached to an amino radical. The term aralkylamino further denotes“monoaralkyl monoalkylamino” containing one aralkyl radical and onealkyl radical attached to an amino radical.

[0136] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one, two or three rings wherein such ringsmay be attached together in a pendent manner or may be fused. The term“aryl” embraces aromatic radicals such as phenyl, naphthyl,tetrahydronaphthyl, indane and biphenyl. Said “aryl” group may have 1 to3 substituents termed “heteroaryl” such as heteroarylamino,N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio,alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl,monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy,haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl,hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl,aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl,partially saturated heterocyclyl, heteroaryl, heteroaryloxy,heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,heteroarylalkenyl, carboalkoxy, carboaralkoxy, cyano, andcarbohaloalkoxy.

[0137] The term “heterocyclic” alone or in combination refers to anonaromatic cyclic group that can include alkyl moieties which may besubstituted, and wherein there is at least one heteroatom, such asoxygen, sulfur, nitrogen, or phosphorus in the ring. Nonlimitingexamples are morpholine, piperidine, piperazine, pyrrolidine, azetidine,and tetrahydrofuran. The heterocyclic group can be optionallysubstituted with one or more moieties selected from the group consistingof hydroxyl, acyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phophonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Greene, et al.,“Protective Groups in Organic Synthesis,” John Wiley and Sons, SecondEdition, 1991, hereby incorporated by reference.

[0138] The term “alditol” as referred to herein, and unless otherwisespecified, refers to a carbohydrate in which the aldehyde or ketonegroup has been reduced to an alcohol moiety. The alditols of the presentinvention can also be optionally substituted or deoxygenated at one ormore positions. Exemplary substituents include hydrogen, halo,haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives,alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl,ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl,thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid,phosphonate, or any other viable functional group that does not inhibitthe pharmacological activity of this compound. Particular exemplarysubstituents include amine and halo, particularly fluorine. Thesubstituent or alditol can be either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Second Edition, 1991, hereby incorporated by reference. Thealditol may comprise 3, 4, 5, 6, or 7 carbons. Examples of usefulalditols are those derived from reduction of monosaccharides, includingspecifically those derived from the reduction of pyranose and furanosesugars.

[0139] The term “carbohydrate” as referred to herein, and unlessotherwise specified, refers to a compound of carbon, hydrogen, andoxygen that contains an aldehyde or ketone group in combination with atleast two hydroxyl groups. The term “carbohydrate lactone” represents acarbohydrate, wherein the anomeric hydroxy group has been formallyoxidized to a carbonyl group thus forming a substituted or unsubstitutedcyclic ester or lactone. The carbohydrates and carbohydrate lactones ofthe present invention can also be optionally substituted or deoxygenatedat one or more positions. Carbohydrates and carbohydrate lactones thusinclude substituted and unsubstituted monosaccharides, disaccharides,oligosaccharides, and polysaccharides. The saccharide can be an aldoseor ketose, and may comprise 3, 4, 5, 6, or 7 carbons. In one embodimentthey are monosaccharides. In another embodiment they can be pyranose andfuranose sugars. They can be optionally deoxygenated at anycorresponding C-position, and/or substituted with one or more moietiessuch as hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino,amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl,sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide,phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime,hydrazine, carbamate,

[0140] The term “carbonyl” or

[0141] denotes a carbon radical having two of the four covalent bondsshared with an oxygen atom. The term “carboxy” embraces a hydroxylradical, attached to one of two unshared bonds in a carbonyl group. Theterm “aldoxy carbonyl” denotes a carbon radical having two of the fourcovalent bonds shared with an oxygen atom, and a third covalent bondshared with another oxygen, also denoted by

[0142] phosphonic acid, phosphonate, or any other viable functionalgroup that does not inhibit the pharmacological activity of thiscompound. Particular exemplary substituents include amine and halo,particularly fluorine. The substituent, carbohydrate, or carbohydratelactone can be either unprotected, or protected as necessary, as knownto those skilled in the art, for example, as taught in Greene, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991, hereby incorporated by reference.

[0143] The term “carboxyalkyl” denotes a carboxy group attached to analkyl group.

[0144] The term “alkoxycarbonyl” denotes a radical having the formulaalkyl—O—C(O)—, wherein alkyl is defined herein.

[0145] The term “cyano” radical denotes a carbon radical having three offour covalent bonds shared by a nitrogen atom.

[0146] The term “halo” and “halogen” means halogens such as fluorine,chlorine, bromine or iodine atoms.

[0147] The term “hydroxyalkyl” embraces radicals wherein any one or moreof the alkyl carbon atoms is substituted with a hydroxyl. Specificallyembraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkylradicals.

[0148] The term “aralkyl” as used herein, and unless otherwisespecified, refers to an aryl group as defined above linked to themolecule through an alkyl group as defined above.

[0149] The term “alkoxy” as used herein, and unless otherwise specified,refers to a moiety of the structure—O—alkyl, wherein alkyl is as definedabove.

[0150] The term “amino” includes primary, secondary, and tertiaryamines. An amino moiety can be represented generally by theformula—NR¹R², wherein R¹ and R² are independently hydrogen orsubstituted or unsubstituted alkyl.

[0151] The term “aminoalkyl” denotes an amino group attached to an alkylgroup, for example—alkyl-NH₂.

[0152] The term “therapeutically effective amount” shall mean thatamount of drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought.

[0153] The term “pharmaceutically acceptable salts” refer to salts orcomplexes that retain the desired biological activity of the compoundsof the present invention and exhibit minimal undesired toxicologicaleffects. Nonlimiting examples of such salts are (a) acid addition saltsformed with inorganic acids (for example, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, nitric acid, and the like), andsalts formed with organic acids such as acetic acid, oxalic acid,tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid,tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, naphthalenedisulfonic acid, andpolygalcturonic acid; (b) base addition salts formed with metal cationssuch as zinc, calcium, bismuth, barium, magnesium, aluminum, copper,cobalt, nickel, cadmium, sodium, potassium, and the like, or with acation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine,tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and(b); e.g., a zinc tannate salt or the like. Also included in thisdefinition are pharmaceutically acceptable quaternary salts known bythose skilled in the art, which specifically include the quaternaryammonium salt of the formula —NR⁺A⁻, wherein R is as defined above and Ais a counterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

[0154] In cases where compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts may be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including, sulfate, nitrate, bicarbonate, and carbonatesalts.

[0155] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

[0156] It is appreciated that compounds of the present invention havinga chiral center may exist in and be isolated in optically active andracemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, diastereomeric, polymorphic, or stereoisomeric form,or mixtures thereof, of a compound of the invention, which possess theuseful properties described herein, it being well known in the art howto prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

[0157] Examples of methods to obtain optically active materials areknown in the art, and include at least the following.

[0158] i) physical separation of crystals—a technique wherebymacroscopic crystals of the individual enantiomers are manuallyseparated. This technique can be used if crystals of the separateenantiomers exist, i.e., the material is a conglomerate, and thecrystals are visually distinct;

[0159] ii) simultaneous crystallization—a technique whereby theindividual enantiomers are separately crystallized from a solution ofthe racemate, possible only if the latter is a conglomerate in the solidstate;

[0160] iii) enzymatic resolutions—a technique whereby partial orcomplete separation of a racemate by virtue of differing rates ofreaction for the enantiomers with an enzyme;

[0161] iv) enzymatic asymmetric synthesis—a synthetic technique wherebyat least one step of the synthesis uses an enzymatic reaction to obtainan enantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

[0162] v) chemical asymmetric synthesis—a synthetic technique wherebythe desired enantiomer is synthesized from an achiral precursor underconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

[0163] vi) diastereomer separations—a technique whereby a racemiccompound is reacted with an enantiomerically pure reagent (the chiralauxiliary) that converts the individual enantiomers to diastereomers.The resulting diastereomers are then separated by chromatography orcrystallization by virtue of their now more distinct structuraldifferences and the chiral auxiliary later removed to obtain the desiredenantiomer;

[0164] vii) first- and second-order asymmetric transformations—atechnique whereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

[0165] viii) kinetic resolutions—this technique refers to theachievement of partial or complete resolution of a racemate (or of afurther resolution of a partially resolved compound) by virtue ofunequal reaction rates of the enantiomers with a chiral, non-racemicreagent or catalyst under kinetic conditions;

[0166] ix) enantiospecific synthesis from non-racemic precursors—asynthetic technique whereby the desired enantiomer is obtained fromnon-chiral starting materials and where the stereochemical integrity isnot or is only minimally compromised over the course of the synthesis;

[0167] x) chiral liquid chromatography—a technique whereby theenantiomers of a racemate are separated in a liquid mobile phase byvirtue of their differing interactions with a stationary phase. Thestationary phase can be made of chiral material or the mobile phase cancontain an additional chiral material to provoke the differinginteractions;

[0168] xi) chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

[0169] xii) extraction with chiral solvents—a technique whereby theenantiomers are separated by virtue of preferential dissolution of oneenantiomer into a particular chiral solvent;

[0170] xiii) transport across chiral membranes—a technique whereby aracemate is placed in contact with a thin membrane barrier. The barriertypically separates two miscible fluids, one containing the racemate,and a driving force such as concentration or pressure differentialcauses preferential transport across the membrane barrier. Separationoccurs as a result of the non-racemic chiral nature of the membranewhich allows only one enantiomer of the racemate to pass through.

[0171] Some of the compounds of the present invention can exist intautomeric, geometric or stereoisomeric forms. The present inventioncontemplates all such compounds, including cis- and trans-geometricisomers, E- and Z-geometric isomers, R- and S-enantiomers,diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof andother mixtures thereof, as falling within the scope of the invention.Pharmaceutically acceptable sales of such tautomeric, geometric orstereoisomeric are also included within the invention. The terms “cis”and “trans” denote a form of geometric isomerism in which two carbonatoms connected by a double bond will each have two high ranking groupson the same side of the double bond (“cis”) or on opposite sides of thedouble bond (“trans”). Some of the compounds described contain alkenylgroups, and are meant to include both cis and trans or “E” and “Z”geometric forms. Some of the compounds described contain one or morestereocenters and are meant to include R, S, and mixtures of R and Sforms for each stereocenter present.

[0172] Some of the compounds described herein may contain one or moreketonic or aldehydic carbonyl groups or combinations thereof alone or aspart of a heterocyclic ring system. Such carbonyl groups may exist inpart or principally in the “keto” form and in part or principally as oneor more “enol” forms of each aldehyde and ketone group present.Compounds of the present invention having aldehydic or ketonic carbonylgroups are meant to include both “keto” and “enol” tautomeric forms.

[0173] Some of the compounds described herein may contain one or moreimine or enamine groups or combinations thereof. Such groups may existin part or principally in the “imine” form and in part or principally asone or more “enamine” forms of each group present. Compounds of thepresent invention having said imine or enamine groups are meant toinclude both “imine” and “enamine” tautomeric forms.

[0174] While it may be possible for the compounds of the invention to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound ofthe invention or a pharmaceutically acceptable salt or solvate thereof,together with one or more pharmaceutically acceptable carriers thereofand optionally one or more other therapeutic ingredient. The carrier(s)must be acceptable in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

[0175] The formulations include those suitable for oral, parenteral(including subcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration although the most suitableroute may depend upon for example the condition and disorder of therecipient. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. All methods include the step of bringing into association acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof (“active ingredient”) with the carrier which constitutesone or more accessory ingredients. In general, the formulations areprepared by uniformly and intimately bringing into association theactive ingredient with liquid carriers or finely divided solid carriersor both and then, if necessary, shaping the product into the desiredformulation.

[0176] Formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

[0177] A tablet may be made by compression or molding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

[0178] Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampuls and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example, saline, water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

[0179] Formulations for rectal administration may be presented as asuppository with the usual carriers such as cocoa butter or polyethyleneglycol.

[0180] Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

[0181] Preferred unit dosage formulations are those containing aneffective dose, as hereinbelow recited, or an appropriate fractionthereof, of the active ingredient.

[0182] It should be understood that in addition to the ingredientsparticularly mentioned above, the formulations of this invention mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

[0183] The compounds of the invention may be administered orally or viainjection at a dose of from 0.001 to 2500 mg/kg per day. The dose rangefor humans is generally from 0.005 mg to 10 g/day. Tablets or otherforms of presentation provided in discrete units may convenientlycontain an amount of compound of the invention which is effective atsuch dosage or as a multiple of the same, for instance, units containing5 mg to 500 mg, usually around 10 mg to 200 mg.

[0184] The compounds of the invention are preferably administered orallyor by injection (intravenous or subcutaneous). The precise amount ofcompound administered to a patient will be the responsibility of theattendant physician. However, the dose employed will depend on a numberof factors, including the age and sex of the patient, the precisedisorder being treated, and its severity. Also, the route ofadministration may vary depending on the condition and its severity.

[0185] The above compounds may be administered alone or in combinationwith other therapeutic drugs, including those used in connection withorgan rejection therapy and particularly including an immunosupressantor other drug mentioned in the Background of the Invention.Specifically, the above compounds may be administered with one or moredrug selected from cyclosporin, tacrolimus (FK506), sirolimus(rapamycin), methotrexate, mycophenolic acid (mycophenolate mofetil),everolimus, azathiprine, steroids and NOX-100.

[0186] In addition, the above compounds are useful in the treatment ofcongestive heart failure, multiple sclerosis, systemic lupus,erythematosis, inflammatory bowel disease (IBD), autoimmune diabetes,diabetic vasculopathies (including diabetic retinopathy and diabeticnephropathy), rhinitis, ischemia-reperfusion injury, cystic fibrosis,chronic obstructive pulmonary disease, glomerulonephritis, bronchialasthma, rheumatoid arthritis, Graves disease, gastrointestinalallergies, and conjunctivitis.

[0187] The compounds of the present invention may also be administeredby use of an intraluminal stent. Although stents are commonly used aspart of an angioplasty procedure, intraluminal stents can be used tomaintain or control any bodily luminal opening. The compound of thepresent invention could be used alone or as part of a compositionallowing for a controlled release of the therapeutically activecompound. The compounds could be coated on the stent or made a part ofthe stent. They may be layered so as to provide limited release of theactive compound, or used in any manner known in the art. See U.S. patentapplication Nos. 20010029660 and 20010032014, herein incorporated byreference in their entirety.

EXAMPLE 1

[0188] Methods for the preparation of the compounds of the invention aredisclosed in U.S. Pat. No. 6,147,250. The following is a method ofproducing Compound A.

[0189] Probucol (5, 9.69 mmol) and methyl 4-chlorobutyrate (3.1 g. 1.4eq) were stirred in DMF (15 mL) and potassium fluoride on alumina (7 g,5 eq) was added. The mixture was stirred at room temperature undernitrogen for 20.5 hours. It was filtered, diluted with ethyl acetate(100 mL), washed with water and brine, dried over sodium sulfate, andevaporated. Chromatography (MPLC, 10% to 80% of dichloromethane inhexanes) gave 0.98 g of methyl4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyrate.

[0190] Methyl4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyrate(0.95 g, obtained above) was dissolved in THI/MeOH/H2O (4:1;1, 15.4 mL)and lithium hydroxide hydrate (0.19 g) was added. The mixture wasstirred at room temperature for four hours and then acidified with 0.3 NHCl. The mixture was poured into brine and extracted with ethyl acetate.The organic phase was dried over sodium sulfate and evaporated to give0.60 g of4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyricacid (Compound A) as a solid.

EXAMPLE 2

[0191] Smooth Muscle Cell Inhibition

[0192] Cultured human aortic smooth muscle cells (AoSMC) were obtainedfrom Clonetics, Inc. and were used below passage 10. Cells were seededin 24-well plates. When cells were 80% confluent, they were madequiescent by adding media containing 0.2% serum (as compared to 5% serumin normal culture media) for 48 hours. The cells were then stimulated by5% serum in the presence or absence of compounds dissolved in DMSO. Toestablish a dose curve and IC₅₀ for each compound, multipleconcentrations (20, 15, 10, 5 μM) were used. Rapamycin (at 1 and 0.1 μM)was used as a positive control for the assay. After a 20 hr incubationwith or without test compounds, ³H-thymidine (0.5 μCi/per well) wasadded to the cells for 4 hours of labeling. Washed cells were then lysedin NaOH and the amount of ³H-thymidine incorporation was determined by ascintillation counter. Table 1 contains the IC₅₀s for compounds A-I.TABLE 1 SMC Proliferation Compound Inhibition (IC₅₀) A 5.5 B 7 C 7.2 D 6E 3.7 I 8

EXAMPLE 3

[0193] Rat Aortic Allograft Model

[0194] Compound A was evaluated for graft arteriosclerosis resultingfrom aortic heterotropic transplantation. This is a model of graftarteriopathy which is the major obstacle to long term success of solidorgan transplantation.

[0195] Donor descending aortas from ACI rats were heterotypicallytransplanted into Lewis rat abdomens in end-to-end fashion with minimalischemic time. 55 rats were assigned to five groups as follows:

[0196] 0 mg/kg/d Compound A(vehicle)(N=10);

[0197] 10 mg/kg/d Compound A (N=10);

[0198] 20 mg/kg/d Compound A (N=10),

[0199] 40 mg/kg/d Compound A (N=10),

[0200] cyclosporin 10 mg/kg/d, PO (N=10); and

[0201] isograft negative control (Lewis-to-Lewis, N=5).

[0202] Compound A was administered subcutaneously to recipient animalsthree days prior to the surgery and once daily for 90 days thereafter.Due to failure to gain weight and skin irritation, the group receiving40 mg/kg/d received this dose for only 13 days. Thereafter, the dose wasreduced to 30 mg/kg/d for 6 days and then further reduced to 5 mg/kg/dfor the remainder of the study.

[0203] On day 90, the allograft segment was removed, fixed in 10%buffered formalin and paraffin embedded. Sections were stained with vonGeisson's elastic stain, and intima-to-media area (IM) ratio and percentluminal narrowing (% LN) were assessed by digital morphometry (See FIGS.1 and 2). Blood was collected at regular intervals throughout the studyand plasma evaluated for compound levels (See FIG. 3).

[0204] The treatment with Compound A was well tolerated at the 10, and20 mg/kg/d doses and animals regained weight post surgery. The grouptreated with the 40 mg/kg/d initially lost weight until the dose wasdropped to 5 mg/kg/d after which time they gained weight similar tovehicle controls. Recipient animals treated with Compound A hadsignificantly lower IM ratio and % LN when compared to the vehicle groupat the 20 mg and 40/30/5 mg/kg/d doses. The group receiving the 40/30/5mg/kg/d dose of Compound A evidenced the highest degree of inhibitiondespite the fact that it received only a 40 mg/kg/d dose for 13 daysprior to dosing down. The percent inhibition of IM ratio in Compound Atreated animals were 11%, 28% and 49%, at the 10, 20 and 40/30/5 dosesrespectively when compared to vehicle control animals. The percentinhibition of the % LN was 22%, 33% and 52% at the 10, 20 and 40/30/5treated animals when compared to vehicle control animals. Cyclosporin(CsA) inhibited IM and % LN by 98% and 94% compared with vehiclecontrol. After 90 days of dosing, the trough plasma levels were 10, 18and 28 μM for the 10, 20 and 40/30/5 mg/kg/d doses, respectively.

[0205] Compound A evidenced dose-dependent inhibition of aorticneointimal growth, a feature of graft arteriosclerosis associated withchronic transplantation rejection. At the 20 mg/kg/d dose it wasefficacious without grossly discernable toxic side effects. The 40/30/5mg/kg/d dose given for 14 days resulted in the greatest degree ofinhibition suggesting that an initial high dose of compound may providelong term beneficial effects.

We claim:
 1. A method for treating transplant rejection in a mammalcomprising administering to said mammal an effective amount of acompound of formula

or a pharmaceutically acceptable salt thereof wherein: Y is a bond or

R₁, R₂, R₃, and R₄ are independently selected from the group consistingof hydrogen, hydroxy, C₁₋₁₀alkyl, aryl, heteroaryl, C₁₋₁₀alkaryl, andaryl C₁₋₁₀alkyl, wherein all nonhydrogen and hydroxy substituents mayoptionally be substituted from one or more of the group selected fromC₁₋₁₀alkyl, halogen, nitro, amino, halo₁₋₁₀alkyl, C₁₋₁₀alkylamino,diC₁₋₁₀alkylamino, acyl, and acyloxy; Z is selected from the groupconsisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl,aryl, heteroaryl, C₁₋₁₀alkaryl, arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylaminoC₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carboxy, carbohydrate group,carbohydrate lactone group, and an alditol group wherein all mayoptionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,halo, nitro, amino, cyano, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl,acyloxy, COOH, COOR₇, OC(O)R₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇,CONR₇R₇, NHC(O)O—R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇,PO₂H₂P(O)(OH)R₇, P(O)(OR₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl,and cyclic phosphate, wherein when possible, all may be optionallysubstituted by one or more R₆; R₆ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and R₈ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, and carboxy; wherein two R₇ groups may cometogether to form a 4 to 7 membered ring.
 2. A method for treatingtransplant rejection in a mammal comprising administering to said mammalan effective amount of a compound of formula

or a pharmaceutically acceptable salt wherein: Y is a bond; Z isselected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl, aryl, heteroaryl, C₁₋₁₀alkaryl,arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylaminoC₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carbohydrate group, carbohydratelactone group, and an alditol group wherein all may optionally besubstituted by one or more R₅; R₅ is independently selected from thegroup selected from hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, halo, nitro,amino, cyano, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl, acyloxy, COOH,COOR₇, OC(O)R₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇,NHC(O)O—R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, PO₂H₂P(O)(OH)R₇, P(O)(OR₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, andcyclic phosphate, wherein when possible, all may be optionallysubstituted by one or more R₆; R₆ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and R₈ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, and carboxy; wherein two R₇ groups may cometogether to form a 4 to 7 membered ring.
 3. The method of claim 2,wherein: Z is selected from the group consisting of C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, and carboxyC₁₋₆alkyl, wherein allmay optionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, amino, halo, COOH, COOR₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, OSO₃H, SO₃H, SO₂NHR₇,SO₂NR₇R₇, P(O)(OH)OR₇, P(O)(OH)R₇, P(O)HR₇, P(OR₇)₂, P(O)R₇(OR₇), OPO₃H,PO₃H₂, and hydroxymethyl, wherein when possible, all may be optionallysubstituted by one or more R₆; R₆ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkoxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, andC₁₋₆alkylcarboxyC₁₋₆alkyl, wherein all may be optionally substituted byone or more R₈; and R₈ is independently selected from the groupconsisting of hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino,cyano, and carboxy.
 4. The method of claim 3, wherein: Z is C₁₋₆alkyl,optionally substituted by one or more R₅; R₅ is independently selectedfrom the group consisting of halo, COOH, COOR₇, CONH₂, CONHR₇, CONR₇R₇,and amino; R₇ is independently selected from the group consisting ofC₁₋₆alkyl, carboxyC₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, andC₁₋₆alkylcarboxyC₁₋₆alkyl, wherein all may be optionally substituted byone or more R₈; and R₈ is independently selected from the groupconsisting of hydroxy, halo, amino, and carboxy.
 5. The method of claim4, wherein: Z is C₁₋₆alkyl, optionally substituted by one or more R₅;and R₅ is COOH.
 6. The method of claim 5, wherein the compound or itspharmaceutically acceptable salt is selected from the group consistingof


7. The method of claim 6, wherein the compound or its pharmaceuticallyacceptable salt is
 8. The method of claim 2, wherein: Z is an alditol,optionally substituted with one or more R₅; and R₅ is independentlyselected from the group consisting of halo, amino, carboxy,diC₁₋₆alkylamino, and C₁₋₆alkylamino.
 9. The method of claim 8, whereinthe compound or its pharmaceutically acceptable salt is selected fromthe group consisting of


10. The method of claim 2, wherein: Z is a carbohydrate or acarbohydrate lactone, optionally substituted by one or more R₅; and R₅is independently selected from the group consisting of halo, amino,carboxy, diC₁₋₆alkylamino, acyloxy, and C₁₋₆alkylamino.
 11. The methodof claim 10, wherein the compound or its pharmaceutically acceptablesalt is selected form the group consisting of


12. The method of claim 2, wherein: Z is selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, Cl ₆alkylaminoC₁₋₆alkyl,C₁₋₆dialkylaminoC₁₋₆alkyl, and aminoC₁₋₆alkyl, wherein all mayoptionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,acyloxy, halo, nitro, amino, cyano, C₁₋₆alkylamino, diC₁₋₆alkylamino,acyl, acyloxy, COOH, COOR₇, OC(O)R₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂,C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇,P(O)(OH)OR₇, P(O)HR₇, P(O)(OH)R₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂,hydroxymethyl, and cyclic phosphate, wherein when possible, all may beoptionally substituted by one or more R₆; R₆ is independently selectedfrom the group consisting of hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy,halo, amino, cyano, haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₁₀loalkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, carboxyC₁₋₆alkyl,C₁₋₆alkylcarboxyC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R_(8;) and R₈ is independently selected fromthe group consisting of hydroxy, halo, amino, and carboxy
 13. The methodof claim 12, wherein the compound or its pharmaceutically acceptablesalt is selected form the group consisting of


14. The method of claim 2, wherein: Z is selected from the groupconsisting of C₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkaryl, arylC₁₋₆alkyl,heteroarylC₁₋₆alkyl, heterocycle, and heterocyclC₁₋₆alkyl, wherein allmay optionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,acyloxy, halo, nitro, amino, cyano, C₁₋₆alkylamino, diC₁₋₆alkylamino,acyl, acyloxy, COOH, COOR₇, OC(O)R₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂,C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇,P(O)(OH)OR₇, P(O)HR₇, P(O)(OH)R₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂,hydroxymethyl, and cyclic phosphate, wherein when possible, all may beoptionally substituted by one or more R₆; R₆ is independently selectedfrom the group consisting of hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy,halo, amino, cyano, haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₆alkyl,C₁₋₆alkylcarboxyC₁₋₆alkyl, C₁₋₆alkylcarboxyC₁₋₆aryl, heterocycle,heterocyclC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and R₈ is independently selected from thegroup consisting of hydroxy, halo, amino, and carboxy; wherein two R₇groups may come together to form a 4 to 7 membered ring.
 15. A methodfor treating transplant rejection in a mammal comprising administeringto said mammal an effective amount of a compound of formula

or a pharmaceutically acceptable salt wherein:

Z is selected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, hydroxyC₁₋₁₀alkyl, aryl, heteroaryl, C₁₋₁₀alkaryl,aryl₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylaminoC₁₋₁₀alkyl, carboxyC₁₋₁₀alkyl,C₁₋₁₀dialkylaminoC₁₋₁₀alkyl, aminoC₁₋₁₀alkyl, heterocycle,heterocyclC₁₋₁₀alkyl, R₇NH, R₇R₇N, carboxy, carbohydrate group,carbohydrate lactone group, and an alditol group wherein all mayoptionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,halo, nitro, amino, cyano, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino, acyl,acyloxy, COOH, COOR₇, OC(O)R₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇,CONR₇R₇, NHC(O)O—R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇,PO₂H₂P(O)(OH)R₇, P(O))OR₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl,and cyclic phosphate, wherein when possible, all may be optionallysubstituted by one or more R₆; R₆ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, haloC₁₋₁₀alkyl, C₁₋₁₀alkylamino, diC₁₋₁₀alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₁₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₁₋₁₀aryl, heterocycle,heterocyclC₁₋₁₀alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and R₈ is independently selected from thegroup consisting of hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, acyloxy, halo,nitro, amino, cyano, and carboxy; wherein two R₇ groups may cometogether to form a 4 to 7 membered ring.
 16. The method of claim 15,wherein: Z is selected from the group consisting of C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, and carboxyC₁₋₆alkyl, wherein allmay optionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, amino, halo, COOH, COOR₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, OSO₃H, SO₃H, SO₂NHR₇,SO₂NR₇R₇, P(O)(OH)OR₇, P(O)(OH)R₇, P(O)HR₇, P(OR₇)₂, P(O)R₇(OR₇), OPO₃H,PO₃H₂, and hydroxymethyl, wherein when possible, all may be optionallysubstituted by one or more R₆; R₇ is independently selected from thegroup consisting of C₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkoxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, andC₁₋₆alkylcarboxyC₁₋₆alkyl, wherein all may be optionally substituted byone or more R₈; and R₈ is independently selected from the groupconsisting of hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino,cyano, and carboxy.
 17. The method of claim 16, wherein: Z is C₁₋₆alkyl,optionally substituted by one or more R₅; R₅ is independently selectedfrom the group consisting of halo, COOH, COOR₇, CONH₂, CONHR₇, CONR₇R₇,and amino; R₇ is independently selected from the group consisting ofC₁₋₆alkyl, carboxyC₁₋₆alkyl, and C₁₋₆alkylcarboxyC₁₋₆alkyl, wherein allmay be optionally substituted by one or more R₈; and R₈ is independentlyselected from the group consisting of hydroxy, halo, amino, and carboxy.18. The method of claim 17, wherein: Z is C₁₋₆alkyl, optionallysubstituted by one or more R₅; and R₅ is COOH.
 19. The method of claim18, wherein the compound or its pharmaceutically acceptable salt isselected from the group consisting of


20. The method of claim 19, wherein the compound or its pharmaceuticallyacceptable salt is


21. The method of claim 15, wherein: Z is selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylaminoC₁₋₆alkyl,and aminoC₁₋₆alkyl, wherein all may optionally be substituted by one ormore R₅; R₅ is independently selected from the group selected fromhydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, nitro, amino, cyano,C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, acyloxy, COOH, COOR₇, OC(O)R₇,CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂, C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H,SO₃H, SO₂NHR₇, SO₂NR₇R₇, P(O)(OH)OR₇, P(O)HR₇, P(O)(OH)R₇, P(OR₇)₂,P(O)R₇(OR₇), OPO₃H, PO₃H₂, hydroxymethyl, and cyclic phosphate, whereinwhen possible, all may be optionally substituted by one or more R₆; R₆is independently selected from the group consisting of hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy, halo, amino, cyano, haloC₁₋₆alkyl,C₁₋₆alkylamino, diC₁₋₆alkylamino, acyl, and acyloxy; R₇ is independentlyselected from the group consisting of C₁₋₆alkyl, C₂₋₁₀loalkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl,carboxyC₁₋₆alkyl, C₁₋₆alkylcarboxyC₁₋₆alkyl, and heteroaryl, wherein allmay be optionally substituted by one or more R₈; and R₈ is independentlyselected from the group consisting of hydroxy, halo, amino, and carboxy22. The method of claim 21, wherein the compound or its pharmaceuticallyacceptable salt is


23. The method of claim 15, wherein: Z is selected from the groupconsisting of C₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkaryl, arylC₁₋₆alkyl,heteroarylC₁₋₆alkyl, heterocycle, and heterocycIC₁₋₆alkyl, wherein allmay optionally be substituted by one or more R₅; R₅ is independentlyselected from the group selected from hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,acyloxy, halo, nitro, amino, cyano, C₁₋₆alkylamino, diC₁₋₆alkylamino,acyl, acyloxy, COOH, COOR₇, OC(O)R₇, CH(OH)R₇, NHR₇, NR₇R₇, C(O)NH₂,C(O)NHR₇, CONR₇R₇, NHC(O)O—R₇, OSO₃H, SO₃H, SO₂NHR₇, SO₂NR₇R₇,P(O)(OH)OR₇, P(O)HR₇, P(O)(OH)R₇, P(OR₇)₂, P(O)R₇(OR₇), OPO₃H, PO₃H₂,hydroxymethyl, and cyclic phosphate, wherein when possible, all may beoptionally substituted by one or more R₆; R₆ is independently selectedfrom the group consisting of hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, acyloxy,halo, amino, cyano, haloC₁₋₆alkyl, C₁₋₆alkylamino, diC₁₋₆alkylamino,acyl, and acyloxy; R₇ is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, aryl, carboxyC₁₋₆alkyl,C₁₋₆alkylcarboxyC₁₋₆alkyl, C₁₋₆alkylcarboxyC₁₋₆aryl, heterocycle,heterocyclC₁₋₆alkyl, and heteroaryl, wherein all may be optionallysubstituted by one or more R₈; and R₈ is independently selected from thegroup consisting of hydroxy, halo, amino, and carboxy; wherein two R₇groups may come together to form a 4 to 7 membered ring.
 24. A methodfor treating transplant rejection in a mammal comprising administeringto said mammal in combination a compound of claim 1, claim 2, or claim15 and one or more compound selected from the group consisting ofcyclosporin, tacrolimus (FK506), sirolimus (rapamycin), methotrexate,mycophenolic acid (mycophenolate mofetil), everolimus, azathiprine,steroids and NOX-100, said combination being administered in an amounteffective to inhibit or modulate transplant rejection.
 25. A compound ofthe formula

or its pharmaceutically acceptable salt thereof.